The effect of time-of-day and sympathetic α1-blockade on orthostatic tolerance

Tolerance time to a standardized orthostatic stressor is markedly reduced in normotensive individuals in the morning. However, the physiological mechanisms that underpin this phenomenon are unknown. The purpose of this study was to examine the role of α1-adrenergic activity on orthostatic tolerance and associated cardiorespiratory and cerebrovascular responses, and to determine whether its endogenous modulation is important in the diurnal variation of orthostatic tolerance. In a four-trial, randomized placebo-controlled crossover experiment, 12 normotensive volunteers (aged 25±1 yrs; mean±SE) completed a 60° head-upward tilt (HUT; 15min or until onset of presyncope) at 06:00 and 16:00h, 90min after the administration of either α1-blockade (prazosin, 1mg20kg body weight) or placebo. Continuous beat-to-beat measurements of middle cerebral blood flow velocity (transcranial Doppler), blood pressure (Finometer), heart rate, stroke volume, cardiac output, and end-tidal carbon dioxide were obtained. Independent of time-of-day, α1-blockade markedly reduced the ability to tolerate a 15-min 60° HUT; tolerance time was 229 shorter compared with the placebo condition (p≤.0001). Moreover, a marked diurnal variation in orthostatic tolerance was evident following α1-adrenergic blockade; e.g., tolerance time in the morning (176±30 s) was lower than in the afternoon (354±75 s; p.04). These findings highlight an important role of α1-sympathetic vasoconstrictor activity in acutely regulating blood pressure and offsetting syncope, especially in the early morning.